Glucose and other sugars react with proteins by a non-enzymatic, post-translational modification process called non-enzymatic glycation. At least a portion of the resulting sugar-derived adducts, called Amadori products, mature to a molecular species that is very reactive, and can readily bind to amino groups on adjacent proteins, resulting in the formation of cross-links between proteins. These sugar derived cross-links can undergo further reaction which lead to the formation of advanced glycated end products (AGEs) some of which may be difficult to break either chemically or enzymatically. Recently a number of classes of compounds have been identified whose members inhibit the formation of the cross-links, or in some cases break the cross-links. These compounds include, for example, the thiazolium compounds described in U.S. Pat. No. 5,853,703. If allowed to accumulate, AGEs, and particularly the resulting cross-links, can lead to several degradations in body function linked with diabetes or age. The above mentioned thiazolium compounds have been used, with success, in animal models for such indications. These indications include loss of elasticity in blood vasculature, loss of kidney function and the appearance of retinopathy.
In addition, as part of studies on these compounds, it has been identified that these thiazolium compounds inhibit the formation of bioactive agents, such as growth factors and inflammatory mediators, that are associated with a number of indications. These agents include vascular endothelial growth factor (VEGF) and TGF[beta]. As a result, a number of new indications have been identified for treatment with agents that inhibit the formation of, or more preferably break cross-links associated with the AGE process. It is not unreasonable to infer that the effects seen are due to the removal of AGE-related molecules that provide a stimulus for the production or release of these growth factors. Removal of such molecules is believed to proceed in part due to the elimination of cross-links that lock the AGE-modified proteins in place. Moreover, such thiazolium compounds also reduce the expression of collagen in conditions associated with excess collagen production.
New methods for administering certain of the above-described thiazolium agents offer researchers additional tools to address pharmacokinetic issues. In addition to having a number of formulations of the thiazolium agents themselves available, it would also be desirable to have prodrugs that are readily converted under physiological conditions to thiazolium agents that can prevent the formation of, and break AGE-crosslinks. Among other things, prodrugs offer the potential for altering certain properties of the agents so that they are more suitable to the conditions in a particular body tissue, cavity or fluid than the drug itself. For example, the prodrug can possess a more advantageous solubility and ionizability profile for a particular body fluid or route of administration than the drug itself. In addition absorption across certain tissues, e.g., skin, mucous membranes can be improved. Such improvements in the physical properties of the agent can contribute to improved delivery of the agent to the site of action, resulting in lower doses of the administered agent. Moreover, having available prodrugs with different physical and chemical properties than the drug itself offers additional chemical entities for preparing pharmaceutical formulations.